Field of the Invention
The present invention relates to a method for the production of chloromethyl cyclopropane and bromomethyl cyclopropane having the formula (1) shown below, as well as corresponding compounds bearing ring substituents. The present method comprises reacting hydroxymethyl cyclopropane (2) or the corresponding substituted compound with methane sulfonic acid chloride or methane sulfonic acid bromide (referred to as "mesyl chloride" or "mesyl bromide") in the presence of a tertiary alkyl amine in a so-called "single-pot" reaction: ##STR2##
Syntheses of haloalkanes from alcohols, particularly primary haloalkanes having a cyclopropyl group bound thereto, tend to result in isomerization (as shown below). For example, in the reaction of the compound of formula (2) with hydrochloric acid, 4-chlorocyclobutane is obtained in a good yield as the main product: ##STR3## (see Lee, C. C., and Cessna, A. J., Can. J. Chem., vol. 58 (1980) 11, 1075-79).
Special measures are required to avoid such isomerization. To suppress this isomerization, the so-called "tosylate' procedure is recommended in the literature (see Weygand/Hilgetag, "Organisch-Chemische Experimentierkunst [The Art of organic Chemistry Experimentation]," 4th edition, 1970, J. Ambrosius Barth, Leipzig, page 232). In contrast to other methods, which lead intermediately via sulfinates or phosphorous acid ester derivatives, the tosylate method requires two steps. First, a toluene sulfonic acid ester (a "tosylate") or a methane sulfonic acid ester (a "mesylate") of the alcohol is produced, and this product is reacted with an alkali metal halide or alkaline earth metal halide in another solvent (e.g., 2-ethoxyethanol or acetone) to provide the alkyl halide product.
The production of the tosylates or mesylates takes place in known manner, by reaction of the alcohols with tosyl chloride or mesyl chloride, in the presence of a strong base, such as pyridine or a pyridine derivative (see the above literature references and the citations therein). For liquid alkyl tosylates and mesylates, post-reaction processing (also referred to as the "work-up") involves ice water washing, extraction and distillation. The pyridine, used in great excess as the solvent, is soluble in water, and thus is completely washed out with water, and is discarded as an aqueous solution. Prior to water washing, the pyridine is sometimes acidified to form an even more water-soluble salt. Processing of this waste water to recover the water-soluble pyridine is very complicated and costly.
The second stage of the tosylate method, reaction of the alkyl tosylate or mesylate with an alkali or alkaline earth halide, also requires a polar, water-soluble solvent. The separation of the polar, water-soluble solvent from the resulting by-product, an alkali or alkaline earth salt of toluene or methane sulfonic acid, is also possible only with very complicated and costly technical measures.
All known tosylate and mesylate methods have a high consumption of chemicals, are technically complicated and time-consuming, and lead to problems in waste disposal. Therefore, a method in which hydroxymethyl cyclopropane is converted to chloromethyl cyclopropane or bromomethyl cyclopropane with mesyl chloride or mesyl bromide which permits easy recovery of the solvents is desirable. There is great interest in such a method, which produces chloromethyl cyclopropane or bromomethyl cyclopropane from hydroxymethyl cyclopropane with little technical effort and without the consumption of environmentally harmful reagents such as pyridine and alcohol glycol ethers. Specifically, such a method which provides chloromethyl cyclopropane or bromomethyl cyclopropane having a purity of more than 85%, preferably more than 90%, is strongly desired because these products are important raw materials for pharmaceutical products.
It has been surprisingly found that in the reaction of a hydroxymethyl cyclopropane with a mesyl halide, the water-soluble pyridine base previously considered necessary can be advantageously replaced with such a trialkylamine, which is either not very soluble or even insoluble in water.
Furthermore, it has been surprisingly found that suitable temperature control and a precisely selected time of mesyl halide addition result in direct formation of chloromethyl cyclopropanes and bromomethyl cyclopropanes in a good yield. That is, the intermediate mesylate does not have to be isolated, but rather, continues to react with the halide present in the reaction mixture to form the target product.